ABSTRACT (PROJECT 4) Evidence from this program project (PPG) demonstrated that defects in genome maintenance cause premature aging in mice. The contribution of genome maintenance to human aging and longevity, however, remains to be established. The main objective of Project 4 has been to translate the PPG?s breakthrough discoveries into the human situation by testing the hypothesis that polymorphic variation at loci involved in genome maintenance (GM) contributes to aging and longevity in humans by altering the GM gene functional networks. Research in Project 4 has led to the discovery of human genetic signatures of genome maintenance associated with longevity and aging: 1) enrichment of rare coding variants predicted to change the function of proteins involved in signaling and repair of DNA damage in centenarians as compared to controls; and 2) enrichment of common non-coding variants predicted to change the expression of genes involved in signaling and repair of, and cellular response to, DNA damage in numerous age-related diseases, including cardiovascular disease, neurodegenerative diseases and a wide range of other chronic diseases and conditions. Our results provide strong evidence that genetic modulation of genome maintenance can exert either beneficial or deleterious effects on lifespan and healthspan in humans. It is imperative that we develop a clearer understanding of the functional genetic control of genome maintenance that shapes human aging and longevity for better strategies to promote healthspan. The experiments outlined in this proposal are aimed at exactly this goal by investigating the mechanistic link between genetic variation in GM genes, longevity, and healthspan through an innovative research strategy combining human genetic discovery, data mining and integration, high-throughput technologies, and cell model systems. The ultimate impact of this project lies in its potential to reveal GM as fundamental mechanisms of aging in humans and as therapeutic targets for multiple age-related diseases in close collaboration with Projects 1, 2, and 3, and Core B.